Several lines of evidence indicate that Type 2 (non-insulin-dependent) diabetes mellitus is a heterogeneous disease that results from a combination of abnormalities in both insulin secretion and insulin action. The causes of decreased insulin secretion in Type 2 diabetes are still not completely understood, but in a subgroup of Type 2 diabetic patients they may be related to an autoimmune destruction of the pancreatic beta-cells. We showed that in Type 2 diabetic patients the presence of GAD65 antibodies is strongly related to the use of insulin therapy. We now propose that GAD65 antibody-positive diabetes that we are observing is a unique subclass of Type 2 diabetes, which is associated with relatively severe insulin deficiency. It is important to note that these cases are all reasonably well documented as Type 2 diabetes rather than Type 1 and those they are older individuals and, clearly, are different than traditional Type 1 diabetes or young adults in regard to their clinical characteristics and needs for insulin. We hypothesize that this subset of older T2DM patients carrying GAD65 antibodies is unique in that is associated with severe insulin deficiency, with HLADQ susceptibility and with the development micro vascular disease. In contrast, diabetic patients who are not GAD65 antibody positive are probably primarily insulin resistant, have elevated blood insulin levels and are at primary risk for macro vascular disease. As a model for understanding the causes of insulin deficiency in GAD65 antibody positive older patients (>50 yr of age), we plan to evaluate the metabolic and genetic abnormalities in GAD65 autoantibody positive T2DM patients and compare these abnormalities with those of a subgroup of GAD65 antibody negative T2DM patients. The characterization of individuals at risk of developing this unique form of Type 2 diabetes is of public health interest because therapeutic strategies could potentially be instituted early enough to prevent the complications related with hyperglycemia and, possibly, the time of onset of insulin requirement. A more appropriate characterization of this subgroup of older Type 2 diabetic patients, presumably of autoimmune pathogenesis, will be of benefit to future research into the etiology, natural history as well as treatment of Type 2 diabetes mellitus.